Validation/Verification of Test MethodsAn FDA Perspective

Laure H. Kairawicz, Ph.D.Senior ScientistExpert Witness

Overview● FD & C Act

– Definition of drugs

– What cGMPs are● Finished Pharmaceuticals

– cGMP regulations

– CGMPs are applied to: ● Drug substances● Drug products● Excipients in formulations● Drug containers and closures

● The Role of USP

– Validation of compendial methods, USP chapter <1225>

– Verification of compendial methods, USP chapter <1226>● Summary

FD & C Act● Section 201(g):

– It defines the concept of drug to include finished drug products as well as components of the drug products such as drug substances or APIs (Active Pharmaceutical Ingredients), and excipients found the formulations

● Section 501(b):

– a drug is regarded as adulterated if:● It is recognized in an official compendium (like USP)● its strength, quality or purity fails to conform to compendial

requirements● Unless the drug is properly labeled

● Section 501(a)(2)(b):

– a drug is considered adulterated or not meetings standards if its:● Manufacture and/or● Processing and/or● Packaging and/or Holding/Storing ● do not conform to cGMP regulations

What are cGMP Regulations?

● 21 CFR Parts 210 and 211

– They apply particularly to the manufacture of finished drug products

– They also include controls, as tests and specifications for their components

– The Components are any ingredient intended for use in the manufacture of a drug product like API and excipients in formulations

● The F D & C Act considers APIs and excipients as drugs...

● The F D & C Act provisions apply to all drugs

● The provisions also include the concept of adulteration within the frame of cGMP regulations

● Interestingly, the FDA did not initiate the creation of cGMP regulations for the manufacture APIs and excipients

● The FDA uses ICH guideline “Q7” or “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients” as a reference for recommendations and expectations of high standards of quality and traceability in the manufacturing process

A Few Examples of cGMP Regulations

● They are found in 21 CFR 211.84

● 21 CFR 211.84 deals with the testing of components, drug product containers, and closures:

– Sub-Section 21 CFR 211.84(a) indicates that each lot of components, drug product containers, and closures should be sampled and tested appropriately then released

– Sub-Section 21 CFR 211.84(d)(2) indicates that each component should be tested for conformity with all appropriate written specifications for quality & purity and strength

– Sub-Section 21 CFR 211.84(d)(3) indicates that containers and closures also should be tested for conformity with all appropriate written specifications

cGMP Regulations: Testing & Records Keeping

● 21 CFR 211.194

● 21 CFR 211.194 deals with laboratory records

– Sub-Section 21 CFR 211.194(a) (2) indicates there should be a clear statement of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability

● A crucial point to remember is that the suitability of all testing methods used should be tested and the results faithfully and accurately recorded under actual conditions of use

● There are different levels of testing and recording of results of analytical testing (HPLC for example)

– Validation (highest level of testing) under actual conditions of use

– Qualification (medium level of testing) under actual conditions of use

– Verification (minimum level of testing) under actual conditions of use

<1225> USP General Information Chapter● <1225> describes the validation of compendial procedures

● The chapter is informational but establishes a reference for the treatment of analytical methods

● General notices abbreviated GN Section 6.30 cites <1225> to be followed for the validation of alternative compendial methods

● <1225> refers to section 501(b) of the FD & C Act which refers to the establishment of assays and specifications through USP/NF as legal standards.

● 21 CFR 211.194(a)(2) exempts validation of methods already established and recognized through USP for example

<1225> Continued

● <1225> describes the typical experiments to be completed for the validation of an analytical method, in particular for HPLC/UPLC/Dissolution etc...

– Accuracy

– Precision

– Specificity or Selectivity (not the same as specificity)

– Detection Limit LOD

– Quantitation Limit (LOQ)

– Linearity

– Range

– Robustness● In practice, the phase of drug development (phases I, II, III) dictates

the tightness of the acceptance criteria set for each section of a validation.

<1226> USP Chapter

● <1226> gives guidance on the verification of compendial procedures or testing methods being performed for the first time

● References the 21 CFR 211.194(a)(2) verification requirements for standard methods

● Verifies a procedure’s suitability under actual conditions of use “for a specified drug substance and/or drug product matrix”

● An important point is :

– Complete revalidation of a compendial method is not required to establish suitability of use

● Verification Requirements (recommendations)

– <1226> guides the evaluation of selected analytical performance characteristics listed in USP <1225> Validation of Compendial Procedures

– Also they are founded on the evaluation of complexity of both procedure and material to which the procedure will be applied.

<1226> USP Chapter Continued

● The evaluation pertains to the only characteristics appropriate for the verification of a particular testing method

● Some of the analytical performance characteristics listed in <1225> may be verified

● If the verification process is not successful then:

– it may be concluded that the analytical method may not be suitable for use with the product being tested

– it may be necessary to develop and validate an equivalent but alternate procedure

– the USP General Chapter <1225> is then revisited

SUMMARY

● The FDA enforces U.S. drug laws and regulations by using:

– FD&C Act, cGMP regulations (CFR Sections 210 and 211 for finished pharmaceuticals)

– USP/NF are used as references in the FD&C Act as official compendia

– General Notices, Monographs, & General Chapters are cited, then they are enforced for compendial articles

● The FDA also guides the Pharmaceutical Industry by recommendations:

– i.e. ICH Q7 cGMPs for APIs

– Recommendations are science-based, but equivalent alternative strategies may be used

– USP General Chapters numbered below 1000 mentioned in General Notices or in Monographs are regarded as enforceable for compendial articles, per Section 501(b) of the FD&C Act.

SUMMARY Continued

● USP General Information Chapters (those numbered above 1000) are generally considered by the FDA to be recommendations and are not enforced

● These may be enforced if cited in General Notices or in Monographs

● The FDA may consider these as recommendations if they are from a recognized source however

● Informational chapters are not enforceable because they are recommendations from recognized authoritative sources

● A method verification strategy should be based on the complexity of the procedure and the material tested

● Only the characteristics appropriate for the verification of the particular procedures require an evaluation

● Method verification is a cGMP requirement for the manufacture of finished pharmaceutical products

SUMMARY Continued

● Method Verification covers established standard tests performed on the finished product, all components (APIs and excipients) along with containers/closures

● <1226> targets primarily analytical tests for drug products and APIs, but its principles of verification could also be applied to test methods for excipients and other components like containers and closures

● Expert Witness Services Encompassing:

● Pharmaceutical and Biotechnology Research Regulation

● FDA Compliance

● R&D Analytical Chemistry Laboratory Experience (designing/running experiments, processing data, reporting results, validations, qualifications and verifications)

● cGMP regulations affecting laboratory records and batch records

● Toxicology and clinical trials● This presentation is based on information found in the FDA/CDER Office of

Compliance and the Office of Manufacturing and Product Quality Presentation – Larry A. Ouderkirk – June 27 2013 – USP PNP Stakeholder Meeting